Antiinflammatory 4,5-diaryl-2-nitroimidazoles

ABSTRACT

Antiinflammatory 4,5-diaryl-2-nitroimidazoles, such as 4,5-bis(4-fluorophenyl)-2-nitroimidazole, useful for treating arthritis and related diseases.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a division of application Ser. No. 018,023, filedMar. 6, 1979, now U.S. Pat. No. 4,199,592, which is acontinuation-in-part of Ser. No. 937,715, filed Aug. 25, 1978, nowabandoned.

BACKGROUND OF THE INVENTION

This invention relates to antiinflammatory imidazoles.

Lombardino, in U.S. Pat. No. 2,707,475 discloses antiinflammatory4,5-diaryl-2-substituted imidazoles.

Doebel, in U.S. Pat. Nos. 3,505,350 and 3,651,080, respectively,discloses antiinflammatory4-alkyl-5-aryl-1-substituted-2-mercaptoimidazoles and4-alkyl-2-alkylthio-5-aryl-1-substituted-imidazoles.

Zauer, K., et al., in Chem. Ber., 106, 1638 (1973) disclose4,5-bis(4-methoxyphenyl)-2-methylthioimidazole and4,5-bis(4-chlorophenyl)-2-methylthioimidazole but do not suggest anyuse.

A number of references, such as Current Sci. India, 17, 184-85 (1948)and Acta. Chem. Acad. Sci. Hung., 79 (2) 197-212 (1973) disclose2-(substituted-thio)-4,5-diphenylimidazoles with substituents such asmethyl, propyl, allyl, and acetonyl.

There is a continuing need for safe and effective antiinflammatoryagents. Inflammation is a disease process characterized by redness,fever, swelling, and pain. Arthritis, in its various forms, is the mostprevalent, chronic, and severe of the inflammatory diseases. Traumaticinjury and infection also involve inflammation, and antiinflammatorydrugs are often used in their treatment. The usefulness of mostcommercial antiinflammatories is limited because of toxicity and adverseside-effects. Many produce gastric irritation and other effects, such aschanges in blood cells and central nervous system. Adreno-corticalsteroids produce gastric irritation and suppression of normal adrenalfunction.

The present invention results from efforts to develop new anti-arthriticcompounds with good antiinflammatory activity and minimal side effectsthat could be more effective in treating arthritis than presentlyavailable drugs.

In addition to antiinflammatory properties, some compounds of thisinvention have demonstrated analgesic activity in a test procedure. Thisadditional property is desirable in treatment of arthritis or relateddiseases; however, such compounds can be employed solely to alleviatepain.

SUMMARY OF THE INVENTION

According to this invention there is provided compounds of formula I,pharmaceutical compositions containing them, and methods of using themto treat arthritis in mammals. ##STR1## where R₁ and R₂ independentlyare ##STR2## with the proviso at least one of R₁ and R₂ must be ##STR3##Y₁ is F, Cl, N(CH₃)₂ or C₁ -C₄ alkoxy; Y₂ is H, F, Cl;

R₃ is H, ##STR4## 2-tetrahydropyranyl, 2-tetrahydrofuranyl, ##STR5## or--SO₂ Ar; R₅ is H or methyl

R₆ is C₁ -C₃ alkyl, benzyl, --CH₂ CH₂ OCH₃ or ##STR6## R₇ is C₁ -C₄alkyl or benzyl; and Ar is ##STR7## where Y ₃ is H, F, Cl, Br, C₁ -C₄alkyl, C₁ -C₄ alkoxy or nitro; or

its pharmaceutically suitable acid addition salt where at least one ofR₁ and R₂ is 3-pyridyl, or ##STR8## where Y₁ is N(CH₃)₂ ;

or its pharmaceutically suitable metal salt where R₃ is H.

Some of the compounds of formula I have analgesic activity in additionto antiinflammatory activity.

Pharmaceutical Salts

Pharmaceutically suitable acid addition salts of compounds where one ofR₁ and R₂ is 3-pyridyl and/or ##STR9## where Y₁ is N(CH₃)₂ include thosemade with physiologically acceptable acids and such salts includehydrochloride, sulfate, phosphate and nitrate. Pharmaceutically suitablemetal salts where R₃ is H include those of certain metals, such assodium, potassium, and calcium.

DETAILED DESCRIPTION OF THE INVENTION

Preferred Compounds

Compounds preferred for antiinflammatory activity are those where;independently:

(a) R₁ and R₂ are independently ##STR10## and more preferably ##STR11##or (b) where either R₁ or R₂ is ##STR12## Y₁ is F, Cl, or OCH₃, and morepreferably this constituent is in the para-position; and Y₂ is H; or

(c) R₃ is H.

Examples of suitable compounds are where

R₁ and R₂ are both ##STR13## and R₃ is H; and R₁ and R₂ are both##STR14## and R₃ is H. Synthesis

Compounds of formula I can be prepared by first reacting a4,5-disubstituted imidazole (II) with an appropriate reagent such asbenzyl chloromethyl ether, 2-chlorotetrahydrofuran, dihydropyran,benzenesulfonyl chloride, or ethyl vinyl ether (Equation A). Theresulting 4,5-disubstituted-1-(substituted)imidazole (III) is thentreated with a strong base, such as n-butyl lithium, followed bydinitrogen tetroxide or some other suitable nitrating agent, such asacetyl nitrate or alkyl nitrates (Equation B). Optionally, the choice ofthe protecting group and the workup conditions allows isolation of adesired 4,5-disubstituted-2-nitroimidazole (I, R₃ =H) directly.##STR15##

Alternatively, the R₃ -substituent other than hydrogen of formula I canbe introduced by direct alkylation, acylation, or sulfonylation of thecompounds of formula I where R₃ =H (Equation C). This reaction can becarried out in the absence of presence of a base, such as potassiumcarbonate, pyridine, triethylamine, potassium t-butoxide, methyllithiumor the like. The reaction can be run neat, using the reagent as solvent,or in the presence of an inert solvent, including but not limited todimethylformamide, glyme, THF, pyridine, methylene chloride. Thetemperature of the reaction can be in the range -78° C. to the boilingpoint of the solvent or reagent, if used in excess as the solvent.Examples of alkylating, acylating and sulfonylating agents that can beemployed are alkoxymethyl halides, such as benzyloxymethyl chloride;acyloxymethyl halides, such as chloromethylpivalate; dihydropyran;2-chlorotetrahydrofuran; alkyl chloroformates, such as ethylchloroformate; alkanoic anhydrides and alkanoyl halides, such as aceticanhydride; aroyl halides, such as benzoyl chloride; and arylsulfonylhalides, such as benzenesulfonyl chloride.

The 4,5-disubstituted imidazoles of formula II are commerciallyavailable or may be prepared by techniques well known to those skilledin the art, e.g. H. Bredereck, et al. Ber., 86, 88 (1953) and Ber., 92,338 (1959).

Preparation of pharmaceutically suitable salts of formula I can be inaccordance with well-known techniques of forming salts.

The preparation of these compounds is further illustrated by thefollowing Examples. Parts are by weight and temperatures are in degreescentigrade unless otherwise stated.

EXAMPLE 1 4,5-bis(4-Fluorophenyl)-2-nitroimidazole

A mixture of 124 g (0.484 mole) of 4,5-bis(4-fluorophenyl)imidazole, 84g (1.0 mole) dihydropyran, 20 g boron trifluoride etherate and 1 l ethylacetate was heated at reflux over a weekend. Analysis by TLC (ethylacetate) showed the presence of some unchanged starting material, so 20g (˜0.24 mole) of dihydropyran and 5 g boron trifluoride etherate wasadded and heating was continued overnight. The mixture was then dilutedwith 1 l ether and washed with 10% sodium bicarbonate solution (3×1 l).The organic layer was dried and concentrated on a rotary evaporator. Theresidual solid was recrystallized from methylcyclohexane (removing someinsoluble starting material by filtration) to give 140.2 g (85%) of4,5-bis(4-fluorophenyl)-1-(2-tetrahydropyranyl)imidazole as a whitesolid, mp 149°-152°. F-NMR indicated purity ˜95%. A smaller run waschromatographed to give pure material mp 158°-9°. IR: 3.25μ (═CH); 3.38,3.49μ (sat. CH); 6.22, 6.28, 6.41, 6.60, 6.69μ (C═C and/or C═N); 8.20μ(CF); 9μ region (C--O--C). H-NMR: m(1.4-2.1 δ, 6H); m (3.4 δ, 1H); m(4.0 δ, 1H); m (4.7 δ, 1H); m (6.6-7.5 δ, 8H); s (7.8 δ, 1H). F-NMR: twomultiplets (112.4 25 δ and 116.5 δ, each decouples to a singlet).

To a mixture of 17.0 g (50 mmole) of4,5-bis(4-fluorophenyl)-1-(2-tetrahydropyranyl)imidazole, 6.4 g (55mmole) of N,N,N',N'-tetramethylenediamine and 200 ml of ether cooled to-78° was added dropwise 35 ml (55 mmole) of 1.6 M butyl lithium. Afterstirring for 15 minutes, a solution of 7.9 g (86 mmole) of dinitrogentetroxide in 50 ml of ether was added dropwise. The reaction mixture wasallowed to warm to room temperature and then was distributed between 5%aqueous sodium bicarbonate and ether. The ether was dried and evaporatedto give 21.7 g of an amber oil.

The oil was heated with a mixture of 125 ml of ethanol and 10 ml of 1 Naqueous hydrochloric acid for a few minutes. The reaction mixture wasconcentrated under vacuum.

Chromatography and recrystallization of the product from toluene gave6.1 g of 4,5-bis(4-fluorophenyl)-2-nitroimidazole, m.p. 245°-6° (dec.).The infrared, NMR and F-NMR spectra were consistent with the assignedstructure.

Anal. Calc'd for C₁₅ H₉ F₂ N₃ O₂ : C, 59.81; H, 3.01; N, 13.95. Found:C, 60.21; H, 3.03; N, 13.55.

EXAMPLE 2 4,5-bis(4-Methoxyphenyl)-2-nitroimidazole

By the procedure described in the first paragraph of Example 1,4,5-bis(4-methoxyphenyl)imidazole was converted in 50% yield to4,5-bis(4-methoxyphenyl)-1-(2-tetrahydropyranyl)imidazole, as a whitesolid, m.p. 123°-5°. IR: 3.26μ (═CH); 3.40, 3.53μ (sat. CH); 6.17, 6.32,6.58, 6.68μ (C═C and/or C═N); 8.03μ (aryl-o); 9.60 and 9.72μ (C--O--C).H-NMR: m (1.3-2.1 δ, 6H); two singlets (3.75-3.85 δ, 6H); m (3.2-4.2 δ,2H); ˜t (4.85 δ, 1H); two A₂ B₂ quartets (6.7-7.6 δ, 8H); s (7.85 δ,1H).

Anal. Calc'd. for C₂₂ H₂₄ N₂ O₃ : C, 72.51; H, 6.64; N, 7.69. Found: C,72.32; H, 6.35; N, 7.37.

By the procedure described in Example 1, 14.5 g of4,5-bis(4-methoxyphenyl)-1-(2-tetrahydropyranyl)imidazole was convertedto 4,5-bis(4-methoxyphenyl)-2-nitroimidazole. Chromatography gave ananalytical sample, m.p. 174° (dec.). The infrared and NMR spectra wereconsistent with the assigned structure.

Mass Calc'd for C₁₇ H₁₅ N₃ O₄ : 325.1062. Mass Found: 325.1030.

EXAMPLE 3 4-(4-Fluorophenyl)-5-(2-thienyl)-2-nitroimidazole

To a mixture of 100.0 g. (0.65 mole) of 4-fluorophenylacetic acid and260.0 g of thiophene warmed to 40° C. was added dropwise 150.0 g (0.71mole) of trifluoroacetic anhydride. The reaction mixture was heated atreflux for 3 hours, cooled and then poured into ice. The aqueous layerwas made basic with sodium carbonate and the product was extracted intoether. The combined ether extracts were washed with water and, afterdrying over anhydrous potassium carbonate, were evaporated to give 150.5g of an oil. Crystallization from methanol afforded 94.1 g of2-(4-fluorophenyl)-1-(2-thienyl)ethanone, m.p. 60°-61° C.

Anal. Calc'd for C₁₂ H₉ FOS: C, 65.45; H, 4.09; Found: C, 65.45; H,4.06.

To a solution of 94.1 g (0.43 mole) of2-(4-fluorophenyl)-1-(2-thienyl)ethanone in 700 ml. of ether was addeddropwise a solution of 65.0 g. (0.41 mole of bromine in 140 ml. ofmethylene chloride at room temperature with stirring. The solvent wasremoved under vacuum to give 125.0 g of2-bromo-2-(4-fluorophenyl)-1-(2-thienyl)ethanone.

A mixture of the 2-bromo-2-(4-fluorophenyl)-1-(2-thienyl)ethanone and465 ml. of formamide was heated at reflux under an air condenser for 2hours. The reaction mixture was allowed to cool to room temperature and73.3 g of 4-(4-fluorophenyl)-5-(2-thienyl)imidazole, m.p. 182°-189° C.,collected by filtration. An analytical sample was prepared byrecrystallization from nitromethane, m.p. 200°-202° C. H-NMR: m (6.9-7.7δ, 7H); s (7.8 δ, 1H).

Anal. Calc'd for C₁₃ H₉ N₂ FS: C, 63.93, H, 3.69; N, 11.48. Found: C,63.43; H, 3.82; N, 11.56.

By the procedure discribed in the first paragraph of Example 1, 35.0 gof 4-(4-fluorophenyl)-5-(2-thienyl)imidazole was converted to 56.6 g of4(5)-(4-fluorophenyl)-5(4)-(2-thienyl)-1-(2-tetrahydropyranyl)imidazole.Chromatography on neutral alumina (Woelm activity Grade I) eluting withchloroform gave 30.0 g of pure material as a mixture of two isomers.H-NMR: m (1.4-2.1δ, 6H); m (3.3δ, 1H); m (4.0δ, 1H); m (4.8δ, 1H); m(6.7-7.7δ, 7H); 2s (7.9, 1H).

By the procedure described in Example 1, 30.0 g of4(5)-(4-fluorophenyl)-5(4)-(2-thienyl)-1-(2-tetrahydropyranyl)imidazolewas converted to 4-(4-fluorophenyl)-5-(2-thienyl)-2-nitroimidazole.Purification was effected by dissolving the crude product in aqueous 0.2M potassium hydroxide followed by filtration, then acidification withacetic acid to precipitate an analytical sample, mp. 177.5°-179° C. Theinfrared and NMR spectra were consistent with the assigned structure.

Mass Calc'd. for C₁₃ H₈ FN₃ O₂ S: 289; Mass Found: 289.

Anal. Calc'd. for C₁₃ H₈ FN₃ O₂ S: C, 53.98; H, 2.77; N, 14.53. Found:C, 54.5; H, 2.84; N, 14.4.

EXAMPLE 4 4-(4-Ethoxyphenyl)-5-(4-fluorophenyl)-2-nitroimidazole

A mixture of 24.4 g (86.5 mmoles) of4-(4-ethoxyphenyl)-5-4-fluorophenyl)imidazole, 12.5 g (0.173 mole) ofethyl vinyl ether and 11.2 g (86.8 mmoles) of dichloroacetic acid in 175ml. of tolune was heated at reflux for several hours. After cooling toroom temperature, the reaction mixture was stirred overnight with 85 ml.of 20% aqueous sodium hydroxide. The toluene layer was separated, washedseveral times with water, dried over anhydrous potassium carbonate andthen evaporated to give 21.6 g of4(5)-(4-ethoxyphenyl)-5(4)-(4-fluorophenyl)-1(1-ethoxyethyl)imidazole asan oil. The oil was chromatographed on neutral alumina (Woelm activityGrade I) eluting with chloroform to give 18.0 g of pure material. H-NMR:m (1.0-1.8δ, 9H); q (3.2δ, 2H); q (4.1δ, 2H); q (5.1δ, 1H); m (6.7-7.7δ,8H); s(7.8δ, 1H).

By the procedure described in Example 1, 8.5 g of4(5)-(4-ethoxyphenyl)-5(4)-(4-fluorophenyl)-1-(1-ethoxyethyl)imidazolewas converted to 4-(4-ethoxyphenyl)-5-(4-fluorophenyl)-2-nitroimidazole.The infrared and NMR spectra were consistent with the assignedstructure. Chromatography on Silica-AR with chloroform followed byrecrystallization from 1-chlorobutane gave an analytical sample, mp 176°C. (dec.).

Mass Calc'd. for C₁₇ H₁₄ N₃ FO₃ : 327; Mass Found: 327.

Anal. Calc'd. for C₁₇ H₁₄ N₃ FO₃ : C, 62.39; H, 4.28; N, 12.84. Found:C, 62.4; H, 4.33; N, 12.6.

EXAMPLE 5 4(3,4-Dichlorophenyl)-5-phenyl-2-nitroimidazole

A mixture of 4-(3,4-dichlorophenyl)-5-phenylimidazole (14.5 g, 50mmole), ethyl vinyl ether (10 ml., 100 mmole) and dichloroacetic acid(4.2 ml., 50 mmole) in 100 ml. toluene was heated at reflux under N₂ for1 hour. The cooled reaction mixture was treated with 50 ml. 20% aqueousNaOH, stirred overnight and then left to stand at room temperature fortwo days. The organic phase was washed with water, dried over K₃ CO₃ andconcentrated on a rotary evaporator to give4(5)-(3,4-dichlorophenyl)-5(4)-phenyl 1-(1-ethoxyethyl)imidazole as anoil.

H-NMR 1.13δ (t, J=7Hz, 3H), 1.63δ (d, J=6Hz, 3H), 3.3δ (2q, J=7Hz, 2H),5.13δ (q, J=6Hz, 1H), 7.28-7.8δ (m, 8H), 7.91δ (s, 1H).

The resultant(5)-4-(3,4-dichlorophenyl)-5-(4)-phenyl-1-(1-ethoxyethyl)imidazole (50mmole) and N,N,N'N'-tetramethylethylenediamine (7.5 ml., 55 mmole) in200 ml. THF was cooled to -78° C. under N₂ and treated dropwise with 1.6M n-butyllithium (41 ml. 65 mmole). After stirring for 15 minutes, asolution of dinitrogen tetroxide (7 ml., 110 mmole) in 25 ml. ether wasadded dropwise. The reaction mixture was stirred for 1 hour at and thenallowed to warm to room temperature. The dark mixture was poured into300 ml. saturated aqueous NaHCO₃ and extracted with ether. The combinedorganic extracts were washed with brine, dried and divided into twoportions (3:1). The larger portion was concentrated on the rotaryevaporator, redissolved in 125 ml. ethanol, treated with 30 ml 1 N HCland heated at reflux for 10 minutes. The reaction mixture was cooled toroom temperature and diluted with 35 ml. water. The crystals werecollected, washed with 0.1 N KOH and recrystallized from methylenechloride to give 1.2 g of4-(3,4-dichlorophenyl)-5-phenyl-2-nitroimidazole, mp. 248°-249° C. (D).Infrared and H-NMR spectra were consistent with the assigned structure.MS 333 (M+).

Anal. Calc'd. for C₁₅ H₉ N₃ O₂ Cl₂ : C, 53.91, H, 2.71; N, 12.58; Found:C, 53.86; H, 2.54; N, 12.67.

EXAMPLE 6 4-(4-Fluorophenyl)-5-(3-pyridyl)-2-nitroimidazole

A mixture of 82.0 g (0.6 mole) of methyl nicotinate and 81.0 g (0.6mole) of p-fluorobenzyl cyanide was added dropwise to a solution of 0.9mole of sodium ethoxide in 250 ml. of ethanol at room temperature withstirring. The reaction mixture was heated at reflux overnight, cooledand then poured onto ice-water. The aqueous solution was washed withether and then acidified with concentrated hydrochloric acid. Aprecipitte was collected by filtration and washed with water. A mixtureof the solid with 350 ml. of 48% hydrobromic acid was heated at refluxovernight with stirring. The reaction solution was allowed to cool toroom temperature and crystals were collected by filtration. The crystalswere suspended in water which was then made basic with concentratedammonium hydroxide. The product was extracted into ether, which, afterdrying over anhydrous potassium carbonate, was evaporated to afford 77.9g of fluorobenzyl 3-pyridyl ketones as colorless crystals, mp. 64°-65°C. IR: 6.0 m (C═O). H-NMR: s(4.3δ, 2H); m (6.9-7.6δ, 5H); d/t (8.2, 1H);d/d (8.8δ, 1H); d (9.3δ, 1H).

To a solution of 15.0 g (69.8 mmoles), 4-fluorobenzyl 3-pyridyl ketonein 120 ml. of acetic acid was added dropwise a solution of 12.3 g (76.9mmoles) of bromine in 120 ml. of acetic acid at room temperature withstirring. After stirring overnight, a precipitate of 18.4 g of α-bromo4-fluorobenzyl 3-pyridyl ketone hydrobromide was collected byfiltration.

A mixture of the α-bromo 4-fluorobenzyl 3-pyridyl ketone hydrobromidewith 150 ml. of formamide was heated at reflux with an air condenserunder nitrogen for 2 hours. The reaction mixture was allowed to cool toroom temperature and then poured onto water. The aqueous solution wasmade basic with sodium carbonate and the product extracted into ether.The combined ether extracts were washed with a saturated aqueous sodiumbicarbonate solution, dried over anhydrous potassium carbonate andevaporated to give 7.5 g of 4-(4-fluorophenyl)-5-(3-pyridyl)imidazole.The product was purified by chromatography on neutral alumina (Woelmactivity Grade I) eluting with ethyl acetate/tetrahydrofuran mixturesand then crystallization with ether gave 2.2 g of pure imidazole, mp.154°-156° C. H-NMR: m (6.8-7.58δ, 5H); s(7.6δ, 1H); d/t (7.8δ, 1H); d/d(8.4δ, 1H); d(8.7δ, 1H).

Anal. Calc'd. for C₁₄ H₁₉ FN₃ : C, 70.29; H, 4.18; N, 17.57; Found: C,70.3; H, 4.43; N, 18.0.

Alternatively, a mixture of 28.8 g of α-bromo 4-fluorobenzyl 3-pyridylketone hydrobromide and 40.0 g of potassium acetate in 50 ml of aceticanhydride was stirred overnight at room temperature. The reactionmixture was poured into water and the product extracted into ether. Thecombined ether layers were washed with water and then 10% aqueous sodiumbicarbonate solution. The ether layer were dried over potassiumcarbonate and evaporated. A solution of the residue in 250 ml. of 1 Naqueous hydrochloric acid was heated at reflux for 30 minutes, and aftercooling, made basic with solid sodium carbonate. The product wasextracted into ether and the combined ether extracts evaporated, afterdrying over anhydrous potassium carbonate, to give 16.5 g of α-hydroxy4-fluorobenzyl 3-pyridyl ketone.

The 16.5 g of α-hydroxy 4-fluorobenzyl 3-pyridyl ketone was reacted with12.5 g of ammonium thiocyanate in 1-propanol heated at reflux to give11.3 g of 4-(4-fluorophenyl)-5-(3-pyridyl)-1H-2-imidazolethiol, mp.335°-338° (dec.).

4-(4-Fluorophenyl)-5-(3-pyridyl)-1H-2-imidazolethiol (8.2 g) was addedportionwise to a mixture of 30 ml. of 35% nitric acid at roomtemperature. After stirring overnight, the reaction mixture was dilutedwith water and made basic with sodium carbonate. The product wasextracted into ethyl acetate, which, after drying over potassiumcarbonate was evaporated to yield 5.3 g of4-(4-fluorophenyl)-5-(3-pyridyl)imidazole.

By the procedure described in the first paragraph of Example 4, 1.5 g of4-(4-fluorophenyl)-5-(3-pyridyl)imidazole was converted to4(5)-(4-fluorophenyl)-5-(4) (3-pyridyl)-1-(1-ethoxyethyl)imidazole.Chromatography on neutral alumina (Woelm activity Grade I) eluting withtetrahydrofuran gave pure material. H-NMR: t(1.2δ, 3H); d (1.6δ, 3H); m(3.0-3.4δ, 2H); q (5.1δ, 1H); M (6.8-7.5δ, 5H); t (7.7δ; 1H); s (7.8δ,1H); d/d (8.4δ, 1H); d(8.7, 1H).

By the procedure described in Example 1, 1.0 g of4(5)-(4-fluorophenyl)-5(4) (3-pyridyl)(1-ethoxyethyl)imidazole wasconverted to 4-(4-fluorophenyl)-5-(3-pyridyl)-2-nitroimidazole. Rf=0.19[TLC; silica gel G; ethyl acetate; methanol (90:10)].

EXAMPLE 7 1-Benzoyl-4,5-bis(4-methoxyphenyl)-2-nitroimidazole

To a solution of 4,5-bis(4-methoxyphenyl)-2-nitroimidazole (3 g, 9.2mmole) and triethylamine (3.9 ml., 27.6 mmole) in 30 ml. THF at 0° C.under N₂ was dropwise added a solution of benzoyl chloride (1.2 ml.,10.1 mmole) in 5 ml THF. The reaction mixture was stirred for 8 hours at0° C. and then left in the refrigerator overnight. The reaction was thendiluted with 30 ml ether and filtered. The filtrate was concentrated ona rotary evaporator and chromatographed on Florisil. Recrystallizationfrom methylcyclohexane gave 1.89 g of1-benzoyl-4,5-bis(4-methoxyphenyl)-2-nitroimidazole, mp. 161°-163° C.

IR: 1745 cm⁻¹, H-NMR: 3.73δ (s, 3H), 3.75δ (s, 3H), 6.67-7.83δ (m, 13H),MS 429 (M+)

Anal. Calc'd. for C₂₄ H₁₉ N₃ O₅ : C, 67.12; H, 4.46; N, 9.7. Found: C,67.2; H, 4.40; N, 9.5.

EXAMPLE 8 1-Ethoxycarbonyl 4,5-bis(4-methoxyphenyl)-2-nitroimidazole

To a solution of 4,5-bis(4-methoxyphenyl)-2-nitroimidazole (1.5 g, 4.6mmole) in 25 ml pyridine at 0° C. under nitrogen was dropwise addedethyl chloroformate (1.5 ml. 156 mmole). After 5 hours at 0° C., thereaction mixture was diluted with ethyl acetate, washed 3×1N HCl,3×saturated NaHCO₃, 1×brine, dried and concentrated on a rotaryevaporator. Chromatography on Florsil gave 487 mg. of1-ethoxycarbonyl-4,5-bis(4-methoxyphenyl)-2-nitroimidazole as an oil. IR1795 cm⁻¹. H-NMR: 1.21δ (t, J=7Hz, 3H), 3.7δ (s, 3H), 3.8δ (s, 3H), 4.3δ(q, J=7Hz, 2H), 6.6-7.76 δ(2AB quartets, J=8Hz, 8H); MS 397 (M+).

EXAMPLE 9 1-Acetyl-4,5-bis(4-methoxyphenyl)-2-nitroimidazole

To a solution of 4,5-bis(4-methoxyphenyl)-2-nitroimidazole (3.0 g, 9.22mmole) and triethylamine (7 ml., 51 mmole) in 30 ml. THF at 0° C. underN₂ was dropwise added a solution of acetyl chloride (1.3 ml., 18.4mmole) in 5 ml. THF. After 2 hours at 0° C., the reaction mixture wasdiluted with ethyl acetate washed with 1N HCl, saturated aqueous NaHCO₃and brine, dried and concentrated on a rotary evaporator.Crystallization from ether gave approximately 600 mg. of startingmaterial. HPLC of the mother liquor and crystallization from ether gave1-acetyl 4,5-bis(4-methoxyphenyl)-2-nitroimidazole, mp. 146°-151° C.H-NMR indicates purity >95%. H-NMR: 2.41δ (s, 3H), 3.8δ (s, 3H),6.73-7.56 δ(2AB quartets, J=9Hz, 8H).

EXAMPLE 10 1-(1-Ethoxyethyl)-4,5-bis(4-methoxyphenyl)-2-nitroimidazole

A mixture of 4,5-bis(4-methoxyphenyl)-2-nitroimidazole (1 g, 308 mmole),ethylvinyl ether (1 ml., 6.16 mmole) and dichloroacetic acid (0.3 ml,3.08 mmole) in 10 ml. toluene was heated at reflux under N₂ for 1 hour.The reaction mixture was cooled, 2 ml. ethyl vinyl ether added andheating continued overnight. The cooled reaction mixture was treatedwith 5 ml. 20% NaOH and stirred 24 hours. The organic phase was washedwith water, and brine, dried over K₂ CO₃ and concentrated on a rotaryevaporator. Chromatography on Florisil gave 178 mg.1-(1-ethoxyethyl)-4,5-bis(4-methoxyphenyl)-2-nitroimidazole as an oil.H-NMR: 1.08δ (t, J=7H₂, 3H), 1.65δ (d, J=6H₂, 3H), 3.4δ (q, J=7H, 2H);3.73δ (S, 3H), 3.86δ (S, 3H), 5.9δ (q, J=6H₂, 1H), 6.6-7.36δ (2ABquartets, 8H), MS 352 (M-OC₂ H₅), 325 (M-C₂ H₃ OC₂ H₅).

Other compounds that can be prepared by using the appropriate startingmaterials and the procedures described in the examples and in theSynthesis section are illustrated in the following table.

                  TABLE I                                                         ______________________________________                                         ##STR16##                                                                    R.sub.1       Y.sub.1   Y.sub.2                                                                              R.sub.3                                        ______________________________________                                         ##STR17##    4-Cl      H      H                                               ##STR18##    4-F       H                                                                                     ##STR19##                                      ##STR20##    4-F       H                                                                                     ##STR21##                                      ##STR22##    4-F       H      H                                               ##STR23##    3-Cl      4-Cl   H                                               ##STR24##    3-Cl      4-Cl   H                                               ##STR25##    3-Cl      4-Cl   H                                               ##STR26##    4-OCH.sub.3                                                                             H      H                                               ##STR27##    4-OCH.sub.3                                                                             H      H                                               ##STR28##    4-OCH.sub.3                                                                             H      H                                               ##STR29##    4-OCH.sub.3                                                                             H                                                                                     ##STR30##                                      ##STR31##    4-N(CH.sub.3).sub.2                                                                     H      H                                               ##STR32##    4-OCH.sub.3                                                                             H                                                                                     ##STR33##                                      ##STR34##    4-OC.sub.2 H.sub.5                                                                      H      COCH.sub.3                                      ##STR35##    4-OC.sub.2 H.sub.5                                                                      H                                                                                     ##STR36##                                      ##STR37##    3-Cl      4-Cl                                                                                  ##STR38##                                      ##STR39##    3-Cl      4-Cl                                                                                  ##STR40##                                      ##STR41##    3-Cl      4-Cl   H                                               ##STR42##    3-Cl      4-Cl   H                                               ##STR43##    4-Cl      H      H                                               ##STR44##    3-Cl      4-Cl                                                                                  ##STR45##                                      ##STR46##    4-F       H                                                                                     ##STR47##                                      ##STR48##    4-OCH.sub.3                                                                             H                                                                                     ##STR49##                                      ##STR50##    4-F       H                                                                                     ##STR51##                                     ______________________________________                                    

Dosage Forms

The anti-arthritic and analgesic agents of this invention can beadministered to treat arthritis and/or pain by any means that producescontact of the active agent with the agent's site of action in the bodyof a mammal. The compounds of formula I have anti-arthritic propertiesand in addition some can be used to alleviate pain. They can beadministered by any conventional means available for use in conjunctionwith pharmaceuticals; either as individual therapeutic agents or in acombination of therapeutic agents. They can be administered alone, butare generally administered with a pharmaceutical carrier selected on thebasis of the chosen route of administration and standard pharmaceuticalpractice.

The dosage administered will, of course, vary depending upon knownfactors such as the pharmacodynamic characteristics of the particularagent, and its mode and route of administration; age, health, and weightof the recipient; nature and extent of symptoms, kind of concurrenttreatment, frequency of treatment, and the effect desired. Usually adaily dosage of active ingredient can be about 0.1 to 100 milligrams perkilogram of body weight. Ordinarily 0.1 to 50 and preferably 1.0 to 25milligrams per kilogram per day given in divided doses 2 to 4 times aday or in sustained release form is effective to obtain desired results.

Dosage forms (compositions) suitable for internal administration containfrom about 1 milligram to about 500 milligrams of active ingredient perunit. In these pharmaceutical compositions the active ingredient willordinarily be present in an amount of about 0.5-95% by weight based onthe total weight of the composition.

The active ingredient can be administered orally in solid dosage forms,such as capsules, tablets, and powders, or in liquid dosage forms, suchas elixirs, syrups, and suspensions; it can also be administeredparenterally, in sterile liquid dosage forms.

Gelatin capsules contain the active ingredient and powdered carriers,such as lactose, sucrose, mannitol, starch, cellulose derivatives,magnesium stearate, stearic acid, and the like. Similar diluents can beused to make compressed tablets. Both tablets and capsules can bemanufactured as sustained release products to provide for continuousrelease of medication over a period of hours. Compressed tablets can besugar coated or film coated to mask any unpleasant taste and protect thetablet from the atmosphere, or enteric coated for selectivedisintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring andflavoring to increase patient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose),and related sugar solutions and glycols such as propylene glycol orpolyethylene glycols are suitable carriers for parenteral solutions.Solutions for parenteral administration contain preferably a watersoluble salt of the active ingredient, suitable stablizing agents, andif necessary, buffer substances. Antioxidizing agents such as sodiumbisulfite, sodium sulfite, or ascorbic acid either alone or combined aresuitable stabilizing agents. Also used are citric acid and its salts andsodium EDTA. In addition, parenteral solutions can containpreservatives, such as benzalkonium chloride, methyl- or propyl-paraben,and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington'sPharmaceutical Sciences, E. W. Martin, a Standard reference text in thisfield.

Useful pharmaceutical dosage-forms for administration of the compoundsof this invention can be illustrated as follows:

Capsules

A large number of unit capsules are prepared by filling standardtwo-piece hard gelatin capsules each with 50 milligrams of powderedactive ingredient, 175 milligrams of lactose, 24 milligrams of talc, and6 milligrams magnesium stearate.

Capsules

A mixture of active ingredient in soybean oil is prepared and injectedby means of a positive displacement pump into geletin to form softgelatin capsules containing 50 milligrams of the active ingredient. Thecapsules are washed in petroleum ether and dried.

Tablets

A large number of tablets are prepared by conventional procedures sothat the dosage unit is 50 milligrams of active ingredient, 6 milligramsof magnesium stearate, 70 milligrams of microcrystalline cellulose, 11milligrams of cornstarch and 275 milligrams of lactose. Appropriatecoatings may be applied to increase palatability or delay absorption.

Injectable

A parenteral composition suitable for adminstration by injection isprepared by stirring 1.5% by weight of active ingredient in 10% byvolume propylene glycol and water. The solution is sterilized byfiltration.

Suspension

An aqueous suspension is prepared for oral admininstration so that each5 milliliters contain 10 milligrams of finely divided active ingredient,200 milligrams of sodium carboxymethyl cellulose, 5 milligrams of sodiumbenzoate, 1.0 grams of sorbitol solution, U.S.P., and 0.025 millilitersof vanillin.

Injectable

A parenteral composition suitable for administration by injection isprepared by dissolving 1% by weight of active ingredient in sodiumchloride injection U.S.P. XV and adjusting the pH of the solution tobetween 6 and 7. The solution is sterilized by filtration.

Use

To detect and compare the antiinflammatory activities of compounds inthis series and standard drugs, a test was used based on a standardmodel of arthritis for which there is good correlation with humanefficacy. The model is adjuvant-induced arthritis in rats. FederationProceedings, Vol. 32, No. 2, 1973 "Models Used for the Study and Therapyof Rheumatoid Arthritis"--Symposium of the American Society forPharmacology and Experimental Therapeutics--states "The ratpolyarthritis produced by intradermal injection of a suspension ofMycobacterium tuberculosis in mineral oil (adjuvant) has been usedextensively for the screening of drugs of potential use in rheumatoidarthritis."

Established Adjuvant-Induced Arthritis in Rats

Charles River Lewis male rats (130-150 grams) are injectedsubcutaneously in the plantar area of the right hind paw with 0.1 ml ofadjuvant (Difco heat-killed, lyophilized Mycobacterium butyricumsuspended in mineral oil 5 mg/ml). 20 Nonarthritic controls are injectedwith mineral oil. The animals are held for two weeks to allowdevelopment of arthritis. Paw volumes (uninjected, left hind paw) aremeasured and the adjuvant injected rats are culled and distributed totreatment groups of 10 of equal disease severity. Nonarthritic controlsare distributed to two groups of 10. The rats are given oral doses ofcompound or PVA-Acacia (Polyvinyl Alcohol 1%, Gum acacia, U.S.P. 5%,Methylparaben 0.5%) (10 ml/kg) by gavage on that day and on the sixfollowing days. One day after the last dose the paw volumes (uninjected,left hind paw) are measured using a Ugo Basile Volume Differential MeterModel 7101. ##EQU1##

Dose-response regression lines of the percent decrease are plotted onsemi-log paper by visual fit and the ED50% decrease from control pawvolume is determined by inspection. Data for some of the compounds inthis invention are summarized in Table II.

Compounds from this series were also compared to indomethacin,phenylbutazone, ibuprofen, and aspirin.

                  TABLE II                                                        ______________________________________                                        Established Adjuvant-Induced                                                  Arthritis in Rats (A.A.)                                                      Chemical                                                                      Example        A. A. ED50%                                                    Number         mg/kg                                                          ______________________________________                                        1              0.6 (1.3)                                                      2              2.5                                                            Indomethacin   0.3                                                            Phenylbutazone 10                                                             Ibuprofen      100                                                            Aspirin        305                                                            ______________________________________                                    

Phenylquinone Writhing Test

A standard procedure for detecting and comparing the analgesic activityof compounds in this series for which there is good correlation withhuman efficacy is the standard phenylquinone writhing test modified fromSiegmund, et al., Proc. Soc. Exp. Biol. Med. 95, 729 (1957). A testcompound suspended in 1% methylcellulose was given orally to fasted(17-21 hours) female white mice, 5-20 animals per double blind test.Aqueous (0.01% phenyl-p-benzoquinone) phenylquinone was injectedintraperitoneally at 24 minutes later using 0.20 ml per mouse.Commencing at 30 minutes after the oral administration of the testcompound, the mice were observed for 10 minutes for a characteristicstretching or writhing syndrome which is indicative of pain induced byphenylquinone. The effective analgesic dose for 50% of the mice (ED₅₀)was calculated by the moving average method of Thompson, W. R., Bact.Rev. 11, 115-145 (1947); also time of peak action was determined formany of the compounds. This data is summarized in Table III.

                  TABLE III                                                       ______________________________________                                        Phenylquinone Writhing Test                                                   Chemical                                                                      Example                                                                       Number                ED.sub.50 *                                             ______________________________________                                        1                     59 (30)                                                 2                     <130                                                    ______________________________________                                         *units are in mg/kg at 1/2hour.                                          

"Consisting essentially of" in the present specification is intended tohave its customary meaning: namely, that all specified materials andconditions are very important in practicing the invention but thatunspecified materials and conditions are not excluded so long as they donot prevent the benefits of the invention from being realized.

What is claimed is:
 1. A compound of the formula ##STR52## where Y₁ isF, Cl, N(CH₃)₂ or C₁ -C₄ alkoxy;Y₂ is H, F, Cl; R₃ is H, ##STR53##2-tetrahydropyranyl, 2-tetrahydrofuranyl, ##STR54## or --SO₂ Ar; R₅ is Hor methyl; R₆ is C₁ -C₃ alkyl, benxyl, --CH₂ CH₂ OCH₃ or ##STR55## R₇ isC₁ -C₄ alkyl or benzyl; and Ar is ##STR56## where Y₃ is H, F, Cl, Br, C₁-C₄ alkyl, C₁ -C₄ alkoxy or nitro; or a pharmaceutically suitable acidaddition salt thereof, or a pharmaceutically suitable metal salt thereofwhere R₃ is H.
 2. A compound of claim 1 where Y₁ is F, Cl or OCH₃ and Y₂=H.
 3. A compound of claim 2 where Y₁ is in the para-position.
 4. Acompound of claim 1 where R₃ is H.
 5. A compound of claim 1 where Y₁ isin the para-position and Y₂ is in the meta-position.
 6. A compound ofclaim 3 whereY₁ is F, Cl or OCH₃ ; Y₂ is H; and R₃ is H.
 7. Apharmaceutical composition consisting essentially of a suitablepharmaceutical carrier and an effective antiinflammatory amount of acompound of claim
 1. 8. A pharmaceutical composition consistingessentially of a suitable pharmaceutical carrier and an effectiveantiinflammatory amount of a compound of claim
 2. 9. A pharmaceuticalcomposition consisting essentially of a suitable pharmaceutical carrierand an effective antiinflammatory amount of a compound of claim
 3. 10. Apharmaceutical composition consisting essentially of a suitablepharmaceutical carrier and an effective antiinflammatory amount of acompound of claim
 4. 11. A pharmaceutical composition consistingessentially of a suitable pharmaceutical carrier and an effectiveantiinflammatory amount of a compound of claim
 5. 12. A pharmaceuticalcomposition consisting essentially of a suitable pharmaceutical carrierand an effective antiinflammatory amount of a compound of claim
 6. 13. Amethod of treating arthritis in a mammal which comprises administeringto the mammal an effective antiarthritic amount of a compound ofclaim
 1. 14. A method of treating arthritis in a mammal which comprisesadministering to the mammal an effective antiarthritic amount of acompound of claim
 2. 15. A method of treating arthritis in a mammalwhich comprises administering to the mammal an effective antiarthriticamount of a compound of claim
 3. 16. A method of treating arthritis in amammal which comprises administering to the mammal an effectiveantiarthritic amount of a compound of claim
 4. 17. A method of treatingarthritis in a mammal which comprises administering to the mammal aneffective antiarthritic amount of a compound of claim
 5. 18. A method oftreating arthritis in a mammal which comprises administering to themammal an effective antiarthritic amount of a compound of claim 6.